The labs of the U.S. and foreign P.I.s are actively engaged in studies of the biological and biochemical effects of nitric oxide. Nitric oxide is an endogenous and essential free radical which can react with the superoxide radical anion in an undesired reaction to generate peroxynitrite. These molecules (nitric oxide, superoxide and peroxynitrite) are known to have a variety of toxic effects. The U.S. P.I. is studying the effect of these molecules on lipids, on antioxidant molecules and in a cell model of inflammation and oxidative injury. He is exploring the different aspects of the general hypothesis, first proposed by him, that nitric oxide could be both harmful (by producing peroxynitrite through reaction with superoxide) and helpful (by acting as a radical scavenger to shut down harmful radical chain mechanisms). The specific aims of the FIRCA grant are as follows. (1) Define the role of nitric oxide in regulating mitochondrial production of reactive oxygen and nitrogen species, (2) Examine the impact of reactive nitrogen species on three key mitochondrial target proteins: Mn-superoxide dismutase, cytochrome c and aconitase. These proposed investigations are expected to provide a foundation for understanding the role of nitric oxide in the initiation, propagation and resolution of tissue inflammation.